ACS Chem. Biol. https://doi.org/10.1021/acschembio.9b00616 (2019)

Fatty acids consisting of linear alkyl chains with various degrees of unsaturation can act as bioactive lipids through covalent modification of signaling proteins and modulation of the biophysical properties of membranes. The abundance of very-long-chain fatty acids (VLCFAs) of 20 or more carbons increases during necroptosis, a form of programmed cell death. Parisi et al. found that blocking the accumulation of VLCFAs, which is known to lessen necroptotic cell death, protected cells from membrane permeabilization, whereas increasing VLCFAs caused permeabilization. Consistently, VLCFA C24:0, but not long-chain FA C16:0, induced permeabilization of liposomes that mimic the lipid composition of the plasma membrane. Given the relatively low amounts of VLCFAs that accumulate during necroptosis, the authors speculated that cells must have a mechanism to concentrate the VLCFAs at the membrane to reach sufficient levels to cause permeabilization and promote necroptosis. Indeed, they found that a C20:0-based FA could covalently modify specific proteins, promoting their membrane localization. Inhibiting these modifications led to increased cell viability during necroptosis. These results suggest that VLCFAs promote necroptosis by disrupting membranes through a direct mechanism, as well as an indirect one via protein acylation.

Credit: ACS